Carnitine Deficiency

• What is Carnitine?  Carnitine is an amino acid that is required for the transport of long-chain fatty acids into the mitochondria, the site of beta-oxidation of fatty acids.  About 25 percent of the carnitine required by the body is produced by the liver and kidneys, while the rest is derived from dietary intake. Eg: red meat, poultry, fish and dairy products.  Most of the carnitine in the body is

• Mitochondrial membrane protein that converts longchain fatty acyl-CoA molecules to their corresponding acylcarnitine molecules. • The resulting acylcarnitines are then available for transport into the mitochondrial matrix where they can undergo fatty acid oxidation. • Mitochondrial fatty acid oxidation by the liver provides an alternative source of fuel when glycogen reserves are depleted by fasting. • The pathway fuels ketogenesis for metabolism in peripheral tissues that cannot oxidize fatty acids.

• A condition that prevents the body from converting certain fats called long-chain fatty acids into energy, particularly during periods without food (fasting) • People with this disorder have a faulty enzyme that disrupts carnitine's role in processing longchain fatty acids.

• Three phenotypes of CPT1A deficiency are recognized and suspected based on the following findings: – Hepatic encephalopathy.   Individuals (typically children) present with the laboratory findings of hypoketotic hypoglycemia and sudden onset of liver failure and hepatic encephalopathy precipitated by fasting or fever. The presentation is similar to that seen in Reye syndrome. – Adult-onset myopathy.   In a single individual of Inuit origin who was homozygous for the p.Pro479Leu mutation,the presenting feature was a history of exercise-induced sudden-onset muscle cramping with no indication of hypoglycemia or hepatic failure. – Acute fatty liver of pregnancy.   Fetal homozygosity for CPT1A deficiency has been associated with acute fatty liver of pregnancy.

• Hypoketotic Hypoglycemia • low levels of ketones(products of fat breakdown that are used for energy) • low blood sugar (hypoglycemia)

• Enlarged liver(hepatomegaly) • Muscle weakness • Elevated levels of carnitine in the blood

mutations in the CPT1A gene

production of a defective version of an enzyme called carnitine palmitoyltransferase I long-chain fatty acids from food and fats stored in the body cannot be transported into mitochondria to be broken down and processed

excessive levels of long-chain fatty acids may build up in tissues, damaging the liver, heart, and brain

• condition has an autosomal recessive inheritance pattern

• Treatment of manifestations – prompt treatment of hypoglycemia with intravenous 10% dextrose

• Agents/circumstances to avoid – prolonged fasting – potentially hepatotoxic agents such as valproate and salicylate

• Prevention of primary manifestations – To prevent hypoglycemia, adults need a highcarbohydate, low-fat diet to provide a constant supply of carbohydrate energy and mediumchain triglycerides to provide approximately one-third of total calories (C6-C10 fatty acids do not require the carnitine shuttle for entry into the mitochondrion – infants should eat frequently during the day and have cornstarch continuously at night – fasting should not last more than 12 hours during illness – surgery, or medical procedures

• Prevention of secondary complications – Prevention of hypoglycemia reduces the risk of related neurologic damage

• Surveillance – Pregnant female carriers should be monitored for acute fatty liver of pregnancy – Individuals with CPT1A deficiency should have testing of liver enzymes (AST, ALT, ALP) and liver function (including PT and PTT) at clinic appointments even when asymptomatic and during periods of reduced caloric intake and febrile illness

 Manifests with a decrease of carnitine levels in plasma or tissues, may be associated with genetically determined metabolic conditions, acquired medical conditions, or iatrogenic states.  Disorders of the carnitine cycle or disorders of fatty acid beta-oxidation can cause secondary carnitine deficiency via several mechanisms. Block in fatty acid oxidation contributes to the accumulation of acyl-CoA intermediates. Transesterification with carnitine leads to the formation of acylcarnitine and the release of free CoA. These acylcarnitines are excreted readily in the urine. They inhibit carnitine uptake at the level of the carnitine transporter in renal cells, causing increased carnitine losses in the urine and systemic secondary depletion of carnitine.

 Other genetic conditions that are associated with Fanconi syndrome (eg, Lowe syndrome, cystinosis) may present with secondary carnitine deficiency because of increased renal losses of carnitine.  Lysinuric protein intolerance is associated with an increased excretion of lysine in the urine,

 Acquired medical conditions may affect carnitine homeostasis. Cirrhosis or chronic renal failure may impair the biosynthesis of carnitine. Diets with low carnitine content (eg, lacto-ovo–vegetarian diet) or malabsorption syndromes may cause secondary carnitine deficiency.  It also may be observed in conditions of increased catabolism present in patients with critical illness. Increased losses of carnitine in the urine, which occur in renal tubular

 Preterm neonates are at risk for developing carnitine deficiency because they have impaired reabsorption of carnitine at the level of the proximal renal tubule and immature carnitine biosynthesis.  Iatrogenic causes of secondary carnitine deficiency include several drugs associated

Symptoms of this disease are commonly provoked by prolonged exercise or periods without food. episodic muscle pain Patients with organic acidemia may present with crises consisting of hypoglycemia, ketoacidosis, and hyperammonemia Patients with respiratory chain defects or mitochondrial disorders may present with abnormal fatigability and lactic acidosis associated with exertion The symptoms in newborn are not completely defined.

 Tandem mass spectrometric measurement of serum/plasma acylcarnitines is an initial screening test. Definitive diagnosis is usually made by detection of reduced CPT enzyme activity. Molecular genetic testing of CPT2, the only gene known to be associated with CPT

 Therapy in secondary carnitine deficiency to replenish carnitine and treat the primary metabolic defect with specific diet and other supplements, such as riboflavin, glycine, or biotin  Restriction of lipid intake  Avoidance of fasting situations  Dietary modifications including replacement of long-chain with medium-chain triglycerides supplemented with L-carnitine  Specific protein-restricted diets in patients with aminoacidopathies and organic acidemias